Development Stage: In vitro and retrospective in vivo with each of 8 biomarkers evaluated in up to 100 human tissues: a combination of normal, benign and cancer tissues

Novelty: New class of cancer biomarkers that allow quantitative analysis of tissue sample rather than qualitative. Requires a very small tissue sample (150-200 cells) and no prior knowledge of tumor makeup

Clinical Application: Could be used as a first-line diagnostic tool, potentially as a replacement for or adjunct to traditional histological diagnosis procedures. Could be used in combination with established diagnostic method to achieve increased accuracy

General Description Early detection of cancerous cells is critical to the successful treatment of the disease. Conventional cancer diagnosis is largely based on qualitative morphological criteria. Quantitative tests could greatly increase early detection of malignant cells, improve accuracy of detection, but are currently lacking. Genes occupy specific locations within the cell nucleus which are consistent within a particular cell type across the human population. The spatial arrangement of genes within the nucleus changes during physiological processes including proliferation, differentiation, and disease. In cancer cells, research has shown differences in the spatial locations of specific marker genes when compared to normal cells. This observation makes it possible to distinguish malignant cells by mapping the spatial position of labeled marker genes in the nucleusScientific Progress NCI inventors have established a method to detect abnormal cells in a human sample using the 3D spatial position of one or more genes within the nucleus of the cell. Inventors have identified 8 markers for breast cancer through screening human breast tissue samples and have validated each marker in up to 100 human breast cancer tissue samples. The technology provides sensitive and versatile methods for detecting the disease that are applicable to both solid tumors and blood cancers. Because only small samples (100-200 cells) are required, the need for invasive procedures is reduced. The assay has shown high accuracy and a low false negative rate when tested using known breast cancer and prostate cancer tissue samples. In breast cancer, the false negative rate when analyzing only one gene is 18.2-35.7%, depending on the gene, but is improved to 8% or less by multiplexing with 2 or more genes in combination. The false positive rate is 0-29% for a given gene (average 8.1%) with an average of 3.5% in normal tissue and 14% in benign diseaseFuture Direction

Identification of markers in other cancer types

Strengthen statistical data on the validity of existing markers by increasing the number of tissue sampled tested for each marker

The assay is highly accurate and has a low false negative diagnosis rate

A small tissue sample is required (150-200 cells) limiting the need for invasive procedures for diagnosis

Applicable to both solid tumors and blood cancers

Validated in both breast and prostate cancer, with the potential to be used in other cancers

Weaknesses

The current analysis is low-throughput, with one analysis performed at one time and each analysis takes approximately 6 hours per sample. The automation of nucleus identification would allow this technology to become a high-throughput diagnostic assay, reduce the potential for human error, and allow the technology to be used for the detection of other tumor types

The analysis still needs to be validated in prospective studies in undiagnosed tissue

Nandy K, Gudla PR, Amundsen R, Meaburn KJ, Misteli T, Lockett SJ. Cytometry A. 2012, 81(9):743-754. (PMID: 22899462)Inventor Bios Thomas Misteli, PhD Tom Misteli is an internationally renowned expert in genome cell biology. He trained at the University of London, UK, and the Cold Spring Harbor Laboratory, NY, where he pioneered the use of imaging approaches to study genomes in living cells. His laboratory aims to uncover fundamental principles of higher order genome organization and to apply this knowledge to the development of novel diagnostic and therapeutic strategies for cancer and aging. He has received numerous awards for his work, acts as an advisor for several national and international agencies and serves on numerous editorial boards. He received the Gian Tondury Award, the Gold Medal of The Charles University and the 2012 Flemming Award. He also serves as an Associate Director for the Center for Cancer ResearchKaren Meaburn, PhD Karen Meaburn is an expert on genome positioning in human disease. She gained her PhD from Brunel University, UK, where she discovered and characterized several defects in the organization of the genome in cells derived from patients with various laminopathies, a group of diseases caused by mutations in the nuclear envelope proteins lamin A/C. During her post-doctoral work at the National Institutes of Health, she has focused on genome organization in breast and prostate cancer. These studies provided the first proof-of-principle that the spatial organization of the genome can be used for diagnostic applications